Table Of ContentNational Clinical Guideline Centre
NICE clinical guideline 183
Drug allergy
Diagnosis and management of drug allergy in adults,
children and young people
Clinical guideline 183
Methods, evidence and recommendations
September 2014
Final
Commissioned by the National Institute for
Health and Care Excellence
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Contents
Disclaimer
Healthcare professionals are expected to take NICE clinical guidelines fully into account when
exercising their clinical judgement. However, the guidance does not override the responsibility of
healthcare professionals to make decisions appropriate to the circumstances of each patient, in
consultation with the patient and/or their guardian or carer.
Copyright
National Clinical Guideline Centre, 2014
Funding
National Institute for Health and Care Excellence
National Clinical Guideline Centre, 2014
Drug allergy
Contents
Contents
Contents ............................................................................................................................................ 4
Guideline Development Group members .................................................................................... 8
NCGC technical team members .................................................................................................. 8
Co-optees ................................................................................................................................... 8
Acknowledgements ........................................................................................................................... 9
1 Introduction ............................................................................................................................. 10
2 Development of the guideline ................................................................................................. 12
2.1 What is a NICE clinical guideline? .................................................................................... 12
2.2 Remit .............................................................................................................................. 12
2.3 Who developed this guideline? ....................................................................................... 13
3 Methods .................................................................................................................................. 14
3.1 Developing the review questions and outcomes ............................................................. 14
3.2 Searching for evidence.................................................................................................... 16
3.2.1 Clinical literature search ..................................................................................... 16
3.2.2 Health economic literature search ...................................................................... 16
3.3 Evidence of effectiveness ................................................................................................ 17
3.3.1 Inclusion and exclusion criteria ........................................................................... 18
3.3.2 Methods of combining clinical studies ................................................................ 19
3.3.3 Type of studies ................................................................................................... 21
3.3.4 Appraising the quality of evidence by outcomes ................................................. 22
3.3.5 Grading the quality of clinical evidence............................................................... 23
3.3.6 Risk of bias ......................................................................................................... 23
3.3.7 Inconsistency...................................................................................................... 27
3.3.8 Indirectness ........................................................................................................ 27
3.3.9 Imprecision ........................................................................................................ 27
3.3.10 Evidence statements .......................................................................................... 28
3.4 Evidence of cost effectiveness ........................................................................................ 29
3.4.1 Literature review ................................................................................................ 29
3.4.2 Undertaking new health economic analysis ........................................................ 30
3.4.3 Cost-effectiveness criteria .................................................................................. 30
3.4.4 In the absence of economic evidence ................................................................. 31
3.5 Developing recommendations ........................................................................................ 31
3.5.1 Research recommendations ............................................................................... 32
3.5.2 Validation process .............................................................................................. 32
3.5.3 Updating the guideline ....................................................................................... 32
3.5.4 Disclaimer .......................................................................................................... 32
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3.5.5 Funding .............................................................................................................. 32
4 Algorithm ................................................................................................................................. 33
5 Guideline summary .................................................................................................................. 34
5.1 Key priorities for implementation ................................................................................... 34
Assessment .............................................................................................................................. 34
Documenting and sharing information with other healthcare professionals.............................. 35
Documenting new suspected drug allergic reactions................................................................. 35
Maintaining and sharing drug allergy information..................................................................... 35
Providing information and support to patients ......................................................................... 36
Providing information and support to people who have had specialist drug allergy
investigations ................................................................................................................. 36
Non-specialist management and referral to specialist services.................................................. 36
General .................................................................................................................................... 36
Non-steroidal anti-inflammatory drugs (including selective cyclooxygenase 2 inhibitors) .......... 36
Beta-lactam antibiotics ............................................................................................................. 37
General anaesthesia ................................................................................................................. 37
5.2 Full list of recommendations ........................................................................................... 38
5.3 Key research recommendations ...................................................................................... 43
5.3.1 Designing systems for documenting drug allergy ................................................ 43
5.3.2 Communicating information about drug allergy.................................................. 43
5.3.3 Using selective cyclooxygenase 2 inhibitors in people with previous severe
allergic reactions to non-selective non-steroidal anti-inflammatory drugs .......... 43
5.3.4 Oral antibiotic challenge for diagnosing antibiotic allergy in children .................. 43
6 Assessment .............................................................................................................................. 44
6.1 Review question: What is the clinical and cost effectiveness of clinical probability
scores or algorithms in identifying or excluding drug allergies? ....................................... 44
6.2 Clinical evidence ............................................................................................................. 44
6.2.1 Algorithms.......................................................................................................... 44
6.2.2 Probability scores ............................................................................................... 52
6.2.3 Comparative studies ........................................................................................... 53
6.2.4 Most commonly used algorithm criteria ............................................................. 55
6.3 Economic evidence ......................................................................................................... 55
6.4 Evidence statements....................................................................................................... 56
6.5 Recommendations and link to evidence .......................................................................... 56
7 Measuring serum tryptase after suspected anaphylaxis .......................................................... 61
7.1 Review question: What is the clinical and cost effectiveness of serum tryptase testing
compared with reference standard tests for the diagnosis of an anaphylactic reaction
due to suspected drug allergy? ....................................................................................... 61
7.2 Clinical evidence ............................................................................................................. 62
7.3 Economic evidence ......................................................................................................... 66
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7.4 Evidence statements....................................................................................................... 66
7.5 Recommendations and link to evidence .......................................................................... 66
8 Measuring serum specific immunoglobulin E (IgE) ................................................................... 69
8.1 Review question: What is the clinical and cost effectiveness of serum specific IgE
testing compared with reference standard tests in the diagnosis of drug allergy for
the following drugs? ....................................................................................................... 69
8.2 Clinical evidence ............................................................................................................. 70
8.3 Economic evidence ......................................................................................................... 78
8.4 Evidence statements....................................................................................................... 78
8.5 Recommendations and link to evidence .......................................................................... 79
9 Documenting and sharing information with other healthcare professionals ........................... 81
9.1 Review question: What are the most clinically and cost effective documentation
strategies for communicating drug allergy information across all NHS services to
prevent patients from receiving drugs to which they are allergic? ................................... 81
9.2 Clinical evidence ............................................................................................................. 82
9.2.1 Summary of included studies .............................................................................. 83
9.2.2 Computerised prescribing systems ..................................................................... 94
9.2.3 Pro formas or structured charts .......................................................................... 95
9.2.4 Other documentation strategies ......................................................................... 96
9.3 Economic evidence ......................................................................................................... 97
9.4 Evidence statements....................................................................................................... 97
9.5 Recommendations and link to evidence .......................................................................... 97
10 Providing information and support to patients...................................................................... 102
10.1 Review question 1: What information and support should individuals with suspected
drug allergy or their parents and carers receive? .......................................................... 102
10.2 Review question 2: What information and support should individuals who have had
specialist investigations or their parents and carers receive? ........................................ 102
10.3 Clinical evidence ........................................................................................................... 103
10.3.1 Study summary and quality .............................................................................. 103
10.3.2 Summary of themes ......................................................................................... 106
10.4 Economic evidence ....................................................................................................... 108
10.5 Evidence statements..................................................................................................... 108
10.6 Recommendations and link to evidence ........................................................................ 109
11 Non-specialist management .................................................................................................. 112
Selective COX-2 inhibitors ............................................................................................. 112
11.1 Review question: In patients who have had allergic reactions to NSAIDs what are the
factors that indicate whether they can or cannot tolerate selective COX-2 inhibitors? .. 112
11.2 Clinical evidence ........................................................................................................... 113
11.2.1 Summary of events induced by COX-2 inhibitors in NSAID-sensitive patients
according to the specific drug administered ..................................................... 118
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11.2.2 Prognostic factors............................................................................................. 119
11.3 Economic evidence ....................................................................................................... 121
11.4 Evidence statements..................................................................................................... 121
11.5 Recommendations and link to evidence ........................................................................ 122
12 Referral to specialist drug allergy services ............................................................................. 126
12.1 Review question 1: What is the clinical and cost effectiveness of referral to specialist
drug allergy services for people with suspected allergy to beta-lactam antibiotics? ...... 126
12.2 Review question 2: What is the clinical and cost effectiveness of referral to specialist
drug allergy services for people with suspected allergy to NSAIDs? ............................... 126
12.3 Review question 3: What is the clinical and cost effectiveness of referral to specialist
drug allergy services for people with suspected allergy to local anaesthetics? .............. 126
12.4 Review question 4: What is the clinical and cost effectiveness of referral to specialist
drug allergy services for people with suspected anaphylaxis due to drug allergy during
general anaesthesia? .................................................................................................... 126
12.5 Clinical evidence ........................................................................................................... 127
12.5.1 Benefit of referral ............................................................................................. 127
12.6 Economic evidence ....................................................................................................... 129
12.6.1 People with suspected allergy to beta-lactam antibiotics.................................. 129
12.6.2 People with suspected allergy to NSAIDs .......................................................... 133
12.6.3 People with suspected allergy to local anaesthetics .......................................... 135
12.6.4 People with suspected anaphylaxis due to drug allergy during general
anaesthesia ...................................................................................................... 135
12.7 Evidence statements..................................................................................................... 135
12.8 Recommendations and link to evidence: beta-lactam antibiotics .................................. 135
12.9 Recommendations and link to evidence: NSAIDs........................................................... 138
12.10 Recommendations and link to evidence: local anaesthetics .......................................... 140
12.11 Recommendations and link to evidence: general anaesthesia ....................................... 141
13 Acronyms and glossaries of terms used in the guideline........................................................ 143
13.1 Acronyms and abbreviations ......................................................................................... 143
13.2 Glossary of medical terms ............................................................................................. 144
13.3 Glossary of methodological terms ................................................................................. 145
14 References ............................................................................................................................. 156
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Guideline Development Group members
Name Role
Mike Ardern Jones Consultant Dermatologist
David Cousins Senior Head of Patient Safety for Safe Medication Practice and Medical
Devices, NHS England
Matthew Doyle General Practitioner
George Du Toit Consultant Paediatric Allergist
Mandy East Patient member
Pamela Ewan Consultant Allergist
James Larcombe General Practitioner
Nicola Mundy Patient member
Shuaib Nasser Chair, Consultant Allergist
Alice Oborne Pharmacist
Paul Whitaker Respiratory consultant
Andrew Williams Specialist Nurse
NCGC technical team members
Name Role
Lee Yee Chong Senior Research Fellow (until May 2013)
Margaret Constanti Health Economist (until March 2013)
Kathleen DeMott Research Fellow (until August 2013)
Tamara Diaz Project Manager
Katharina Dworzynski Senior Research Fellow (from June 2013)
Martin Harker Health Economist (from April 2013)
Kate Kelley Guideline Lead, Associate Director (until January 2013)
Grace Marsden Senior Health Economist (from April 2013)
Su Park Research Fellow (from August 2013)
Vicki Pollit Senior Health Economist (until March 2013)
Gill Ritchie Guideline Lead, Associate Director (from February 2013)
Carlos Sharpin Information Scientist
Co-optees
Name Role
Mamidipudi Thirumala Co-optee, Laboratory Pathologist and Consultant Allergist
Krishna
Nigel J N Harper Co-optee, Consultant Anaesthetist
Nick Brown Co-optee, Dentist
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Acknowledgements
Acknowledgements
The development of this guideline was greatly assisted by the following people:
Name Role
Elisabetta Fenu NCGC, Health Economic Lead
Jill Cobb NCGC, Information Scientist
Tom Kenny NIHR Evaluation Trials and Studies Coordinating Centre (NETS CC), Director,
External Relations,
Maggie Westby NCGC, Clinical Effectiveness Lead
Pamela Young NIHR Evaluation Trials and Studies Coordinating Centre (NETS CC), Scientific
Adviser (Identification) - External Relations
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Introduction
1 Introduction
All drugs have the potential to cause side effects, also known as ‘adverse drug reactions’, but not all
of these are allergic in nature. Other reactions are idiosyncratic, pseudo-allergic or caused by drug
intolerance. The British Society for Allergy and Clinical Immunology (BSACI) defines drug allergy as an
adverse drug reaction with an established immunological mechanism. The mechanism at
presentation may not be apparent from the clinical history and it cannot always be established
whether a drug reaction is allergic or non-allergic without investigation. Therefore, this guideline has
defined drug allergy as any reaction caused by a drug with clinical features compatible with an
immunological mechanism.
Hospital Episode Statistics from 1996 to 2000 reported that drug allergies and adverse drug reactions
accounted for approximately 62,000 hospital admissions in England each year. There is also evidence
that these reactions are increasing: between 1998 and 2005 serious adverse drug reactions rose 2.6-
fold.116 Up to 15% of inpatients have their hospital stay prolonged as a result of an adverse drug
reaction.
About half a million people admitted to NHS hospitals each year have a diagnostic ‘label’ of drug
allergy, with the most common being penicillin allergy. About 10% of the general population claim to
have a penicillin allergy;79 this has often been because of a skin rash that occurred during a course of
penicillin in childhood. Fewer than 10% of people who think they are allergic to penicillin are truly
allergic.79 Therefore, penicillin allergy can potentially be excluded in 9% of the population.36,61
Studies have shown that those with a label of penicillin allergy are more likely to be treated with
broad-spectrum antibiotics, such as quinolones, vancomycin, and third-generation cephalosporins
(Lee, 2000)96. Use of broad-spectrum antibiotics is associated with an increased rate of clinical
complications, such as antibiotic resistance and Clostridium difficile leading to increased hospital stay
(Macy,2014)102. Patients in intensive care who developed vancomycin-resistant enterococcus (VRE)
were 5 times more likely to have been treated with vancomycin and third generation cephalosporins
during the previous month (Martinez, 2003)108. Therefore, an unsubstantiated label of penicillin
allergy may lead to the inappropriate use of broad spectrum, non-penicillin antibiotics leading to
antibiotic resistance and in some cases sub-optimal therapy.
Allergic reactions to non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, diclofenac,
naproxen and aspirin are common.61,78 In particular, 5–10% of people with asthma are affected.
About one-third of people with chronic urticaria have severe reactions to NSAIDs, involving
angioedema and anaphylaxis after administration of NSAIDs.34,117
Anaphylaxis-type reactions occur in approximately 1 in 1000 of the general population. Anaphylaxis
during general anaesthesia occurs in between 1 in 10,000–20,000 anaesthetics.46,47 These patients
may be denied general anaesthesia in the future unless a safe combination of drugs can be
identified.115
Major issues identified by this guideline include poor clinical documentation of drug allergy and a
lack of patient information. Computerised primary care record systems are often unable to
distinguish between intolerance and drug allergy and this can lead to a false label of drug allergy,
particularly if the person’s reaction took place many years previously and details about their reaction
have been lost. Furthermore, there is no routine system in place for people to keep a record of their
own drug allergies. This can lead to confusion over which drugs can be taken safely and can result in
people inadvertently taking a drug they are allergic to, particularly when buying over-the-counter
preparations from a pharmacy.
Analysis of patient safety incidents reported to the National Reporting and Learning System between
2005 and 2013 identified 18,079 incidents involving drug allergy. These included 6 deaths, 19 ‘severe
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Description:Healthcare professionals are expected to take NICE clinical guidelines fully into However, the guidance does not override the responsibility of.
